title: (S)-1-(Pent-4'-enoyl)-4-(hydroxymethyl)-azetidin-2-one derivatives as inhibitors of human fatty acid amide hydrolase (hFAAH): synthesis, biological evaluation and molecular modelling.
abstract: A series of lipophilic ester derivatives (2a-g) of (S)-1-(pent-4'-enoyl)-4-(hydroxymethyl)-azetidin-2-one has been synthesised in three steps from (S)-4-(benzyloxycarbonyl)-azetidin-2-one and evaluated as novel, reversible, β-lactamic inhibitors of endocannabinoid-degrading enzymes (human fatty acid amide hydrolase (hFAAH) and monoacylglycerol lipase (hMAGL)). The compounds showed IC50 values in the micromolar range and selectivity for hFAAH versus hMAGL. The unexpected 1000-fold decrease in activity of 2a comparatively to the known regioisomeric structure 1a (i.e. lipophilic chains placed on N1 and C3 positions of the β-lactam core) could be explained on the basis of docking studies into a revisited model of hFAAH active site, considering one or two water molecules in interaction with the catalytic triad.
authors.affiliation: Institut de la Matière Condensée et des Nanosciences (IMCN), Université catholique de Louvain (UCL) , Louvain-la-Neuve , Belgium .
authors.forename: Joséphine
authors.initials: J
authors.lastname: Caruano
authors.forename: Marion
authors.initials: M
authors.lastname: Feledziak
authors.forename: Geoffray
authors.initials: G
authors.lastname: Labar
authors.forename: Catherine
authors.initials: C
authors.lastname: Michaux
authors.forename: Eric A
authors.initials: EA
authors.lastname: Perpète
authors.forename: Giulio G
authors.initials: GG
authors.lastname: Muccioli
authors.forename: Raphaël
authors.initials: R
authors.lastname: Robiette
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Marchand-Brynaert
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001384:Azetidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D020134:Catalytic Domain / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D008994:Monoacylglycerol Lipases / Q000037:antagonists & inhibitors / Q000378:metabolism; D013329:Structure-Activity Relationship; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D001384:Azetidines; D004791:Enzyme Inhibitors; D008994:Monoacylglycerol Lipases; D000099252:Fatty Acid Amide Hydrolases
keywords: docking; fatty acid amide hydrolase; rapid dilution; reversible inhibition; β-lactam